Alkoxy and aryloxy isothiocyanates are well-known versatile, organic intermediates which, by virtue of highly reactive multifunctionalities, can undergo a variety of condensation and cyclization reactions. For instance, Heilbron et al, J. Chem. Soc. 1948, 1340, made use of the ready addition of alkoxycarbonyl isothiocyanate to alpha-aminonitrites in their synthesis related to penicillin and purines. Other useful organic syntheses based on alkoxy and aryloxy isocyanates are set forth by Esmail et al., Synthesis, 301, (1975).
Ethoxycarbonyl isothiocyanate was first prepared by R. E. Doran in 1896 by reacting lead thiocyanate with ethylchloroformate in boiling toluene with relatively poor yields, J. Chem. Soc. 69, 324 (1896). In 1908, Dixon and Taylor reported, J. Chem. Soc. 93, 684 (1908), that methylchloroformate, ethylchloroformate, benzylchloroformate, phenyl chloroformate and o- and p-tolylchloroformate, were reacted with potassium thiocyanate in boiling acetone to form the corresponding isothiocyanate.
One of the reasons for low yields in Dixon et al's method was confirmed by Takamizawa et al to be the simultaneous formation of an unreactive thiocyanate isomer. With ethylchloroformate, two isomers were obtained in about 30% yields while with butylchloroformate the yields were 34% for the isothiocyanate and 21% for the thiocyanate isomer. Yields of 31% for the isothiocyanate and 3.5% for the thiocyanate isomer were obtained with allylchloroformate, it being postulated that the formation of the two isomers was due to the existence of the mesomeric thiocyanate ion and isothiocyanate ion both of which can effect the nucleophilic attack on the carbonyl carbon and cause the thiocyanate and isothiocyanate isomer product. Later workers improved reaction conditions to favor the isothiocyanate formation by adding catalytic amounts of triethylamine and longer reaction times; Goerdeler et al, Chem Ber. 104, 1606 (1971). The use of acetonitrile and ethyl acetate as solvents was reported by Lamon; J. Heterocyclic Chem., 5, 837 (1968); Goerdeler et al, Chem. Ber. 96, 526, (1963). Yields, however, were only up to about 60%. Anders et al, Ger. Pat. No. 1215144, 66, reported the preparation of alkoxy and aryloxy isothiocyanates using silyl isothiocyanate while Goerdeler et al, Chem. Ber. 98, 2954 (1965) disclosed the pyrolysis of thiozolinediones as a means for producing them, see also Schenk, Chem. Ber. 99, 1258 (1966).
In a later publication, Chem. Ber. 116, 2044, (1983), Goerdeler et al reported the use of an aromatic heterocyclic nitrogen catalyst such as pyridine in carbon tetrachloride for the preparation of alkoxythiocarbonyl isothiocyanate, however, the yield was only 52%. Using the propoxy analog, Goerdeler et al obtained only a 13% yield of the corresponding isothiocyanate.
The production of phenoxycarbonyl isothiocyanate is also taught by Babu; J. Heterocyclic Chem. 20, 1127, (1983). Thus, the prior art methods for preparing alkoxy and aryloxy isothiocyanates are ineffective in terms of yields and the formation of the undesirable thiocyanate isomer. Additionally, the use of organic solvents creates costly removal problems and poses serious air emission hazards.
In Lewellyn et al., commonly-assigned U.S. Pat. No. 4,778,921, is described a procedure for the formation of alkoxy and aryloxy isothiocyanates whereby the desired products are obtained in higher yields and purity than when the aforementioned prior art techniques are employed. The process of the Lewellyn et al. invention eliminates the use of organic solvents, and furthermore, since the by-product is alkali metal halide, waste disposal is facilitated.
The Lewellyn et al. process depends on the synthesis of the alkoxy and aryloxyisothiocyanates in an all aqueous medium; it being completely unexpected that such a medium could be employed since both the starting material, i.e., the alkyl or arylhaloformate and product isothiocyanate are normally water-reactive. The use of the aqueous medium was made possible because of the conjoint use therewith of a catalyst comprising a six membered mononuclear or a ten membered fused polynuclear aromatic, heterocyclic compound having 1 or 2 nitrogen atoms as the only hetero atoms in the ring. The unique combination of catalyst and the aqueous medium unexpectedly allowed isothiocyanate formation in high yields and purity. Furthermore, the product isothiocyanate, a strong lachrymator, although isolatable, was not required to be isolated, i.e. it could be reacted in situ with other compounds, e.g., alcohols, amines, mercaptans, etc., to produce many useful derivatives, such as promoters, as is well known to those skilled in this art.
It has now been discovered that the Lewellyn et al. process can be rendered even more useful if an effective amount of a co-catalyst is added to the reaction mixture. Such co-catalysts, comprising salts of alkali metals and alkaline earth metals of weak acids, such as, by way of typical example, sodium acetate, sodium borate, sodium phosphate, sodium carbonate, and the like, have been found to accelerate the rate of formation to the respective alkoxy or aryloxy carbonyl isothiocyanates and to overcome the deleterious effects of impurities, such as thiourea, often encountered in commercial alkali metal and alkaline earth metal thiocyanate solutions. As will be shown hereinafter, judicious selection of the co-catalysts is required because, unexpectedly, compounds such as ammonium salts and quaternary ammonium salts have a decidedly adverse effect.